Somatic inactivation of SMAD4—by mutation, homozygous deletion, or loss of protein expression—is recurrent in CRC, with reported frequencies ranging broadly (commonly ~10% in large cohorts, with study-to-study variability up to ~20% depending on assay and stage) and is enriched in advanced-stage and metastatic disease [36]. This evidence concerns the gene SMAD4 and colorectal carcinoma.